Identifying the mechanisms of leukemia progression

项目总结 自2002年我的实验室在所有急性巨核细胞白血病病例中发现GATA1突变以来 患有唐氏综合症的儿童，我一直站在定义促进 白血病。我广泛地研究了GATA1在正常和恶性造血中的作用，并获得了许多 对包括DYRK1A、ERG和CHAF1B在内的几个21号染色体基因的贡献的洞察 白血病。我的实验室在骨髓增生性肿瘤(MPN)领域也有很好的基础， 尤其是巨核细胞在骨髓纤维化发病机制中的作用 这种疾病的治疗方法。在此R35应用程序中，我建议将我的实验室重点放在未来7年(和 Beyond)了解克隆性造血疾病导致白血病进展的机制。 具体地说，我们将确定和比较儿童和成人疾病发展为急性髓系疾病的方式。 白血病。我们将利用大规模CRISPR/CAS9筛查、动物模型和初级患者样本来 深刻描述转型的机制，重点回答三个问题：1)什么是 促进儿童和成人血液疾病恶性进展的相似和不同的事件？2) 已识别的抑癌基因下游通路的失调如何促进恶性 进展？3)哪些研究或批准的治疗方法可以预防或治疗肿瘤进展？这个 对这些问题的回答将增加我们对癌症的基本认识，揭示新的治疗靶点和 可能有助于阐明化学预防策略。

PROJECT SUMMARY Since 2002 when my laboratory discovered GATA1 mutations in all cases acute megakaryocytic leukemia in children with Down syndrome, I have been at the forefront of defining the specific genetic events that promote leukemia. I have extensively studied the role of GATA1 in normal and malignant hematopoiesis and gained many insights into the contributions of several chromosome 21 genes, including DYRK1A, ERG and CHAF1B, in leukemia. My laboratory is also well established in the field of the myeloproliferative neoplasms (MPNs), especially in the role of megakaryocytes in the pathogenesis of myelofibrosis and the development of new therapies for this disease. In this R35 application, I propose to focus my laboratory over the next 7 years (and beyond) on understanding the mechanisms of leukemia progression from clonal hematopoietic disorders. Specifically, we will identify and compare the ways that pediatric and adult disorders progress to acute myeloid leukemia. We will leverage large scale CRISPR/Cas9 screening, animal models and primary patient samples to deeply characterize the mechanisms of transformation and focus on answering three questions: 1) What are the similar and disparate events that promote malignant progression of pediatric versus adult blood disorders? 2) How does dysregulation of pathways downstream of identified tumor suppressor genes promote malignant progression? 3) Which investigational or approved therapies can prevent progression or treat the tumors? The answers to these questions will increase our basic understanding of cancer, reveal new therapeutic targets and possibly shed light on chemoprevention strategies.